A great amount of effort has been devoted to improving methods and materials for delivery of active agents or therapeutics to patients. Oftentimes, the improvements involve increasing the efficiency of drug delivery, improving drug targeting, improving drug delivery profiles, reducing side-effects, or improving drug stability. In some instances, the improvements are achieved by using an excipient, or more particularly a drug delivery vehicle.
Drug delivery vehicles can be employed with implantable devices, some of which are capable of delivering desired doses of a beneficial active agent over extended periods of time. For example, U.S. Pat. Nos. 5,034,229, 5,557,318, 5,110,596, 5,728,396, 5,985,305, 6,113,938, 6,156,331, 6,375,978, and 6,395,292, the contents of each of which are herein incorporated in their entirety by reference, teach osmotically driven devices capable of delivering an active agent formulation, such as a solution or a suspension, at a desired rate over an extended period of time (i.e., a period ranging from more than one week up to one year or more). Other exemplary implantable devices include regulator-type implantable pumps that provide constant flow, adjustable flow, or programmable flow of beneficial agent formulations, which are available from, for example, Codman of Raynham, Mass., Medtronic of Minneapolis, Minn., and Tricumed Medinzintechnik GmbH of Germany. Further examples of implantable devices are described in U.S. Pat. Nos. 6,283,949, 5,976,109, 5,836,935, and 5,511,355, which are herein incorporated in their entirety by reference. This category of implantable devices can be designed to deliver a desired active agent at therapeutic levels over an extended period of time, and, therefore, drug delivery vehicles incorporated with such devices need to account for such extended periods in vivo.
Examples of active agents or drugs contemplated for use with the present invention are biomolecular material that can act as therapeutics. The delivery of such agents over an extended period of time with an implantable drug delivery system has proven difficult for a number of factors. As it is used herein, the term “biomolecular material” refers to peptides, polypeptides, proteins, nucleic acids, viruses, antibodies, and any other naturally derived, synthetically produced, or recombinantly produced active agent that includes nucleic or amino acid. Among other challenges, two problems must be addressed by the device and the delivery vehicle when seeking to deliver biomolecular material over an extended period of time from an implanted delivery device. First, the biomolecular material must be contained within a formulation that substantially maintains the stability of the material at elevated temperatures (i.e., 37° C. and above) over the operational life of the device. Second, the biomolecular material must be formulated in a way that allows delivery of the biomolecular material from an implanted device into a desired environment of operation over an extended period time. This second challenge has proven particularly difficult where the biomolecular material is included in a flowable composition that is delivered from a device over an extended period of time at low flow rates (i.e., ≦100 μl/day).
Biomolecular material may degrade via one or more of several different mechanisms, including deamidation, oxidation, hydrolysis, disulfide interchange, and racemization. Significantly, water is a reactant in many of the relevant degradation pathways. Moreover, water acts as a plasticizer and facilitates the unfolding and irreversible aggregation of biomolecular materials. To work around the stability problems created by aqueous formulations of biomolecular materials, dry powder formulations of biomolecular materials have been created using known particle formation processes, such as by known lyophilization, spray-drying, or dessication techniques. Though dry powder formulations of biomolecular material have been shown to provide suitable stability characteristics, it would be desirable to provide a formulation that is stable over extended periods of time, and, when delivered via an implantable device, is also flowable and readily deliverable from the implantable device.
In the instances when a drug delivery vehicle uses polymeric excipients, such as povidone, crospovidone, and copovidone, these excipients may lead to oxidation of the active agents in the drug formulations due to the presence of peroxides in the polymer preparations. Some examples of active agents that can be sensitive to oxidation, or oxidation-sensitive active agents, include proteins, peptides, ergot alkaloids, and antibiotics such as doxycycline, metformin and molsidomine. Povidone, crospovidone, and copovidone thus have limited utility as solid excipients in formulations containing oxidation-sensitive active agents. To reduce oxidation, freshly prepared polymeric excipients can be used as they typically have lower peroxide levels than polymer excipients that have been stored for a period of time. However, the use of freshly prepared polymer excipients to prepare drug formulations often involves major logistical problems.
Other nonaqueous drug formulations that can be delivered from an implantable device include biomolecular materials that are stable over extended periods of time at elevated temperatures. The nonaqueous vehicle formulations typically include polymers, solvents, and surfactants. Under certain circumstances, when these formulations are exposed to an aqueous liquid, such as a physiological fluid, within a delivery conduit of a device used to deliver the formulations, the polymer included in the vehicle tends to phase separate from the solvent into the aqueous liquid. As the polymer partitions into the aqueous liquid, the concentration of polymer within the aqueous liquid may increase to such an extent that a highly viscous polymer gel or precipitate is formed within the delivery conduit, resulting in a partial or complete occlusion of the delivery conduit and interfering with the desired operation of the delivery device. The potential for such occlusions increases where the geometry of the conduit is such that aqueous liquid interfaces with the drug formulation in a confined area over a relatively long period of time (e.g., hours or days).
A need therefore exists in the art for methods for reducing peroxide levels in delivery vehicles formed from polymer preparations, particularly in drug formulations comprising oxidation-sensitive active agents. There is a further need for such delivery vehicles to be deliverable from an implantable device with reduced potential for occluding a delivery conduit, while providing enhanced stability to the active agent that is intended for delivery.